In the past few years, the olfactory system has gained attention and popularity as an attractive model system for the formation of neural circuits during mammalian development - a fundamental problem in neurobiology. Olfactory sensory neurons (OSNs) are thought to express only one member from a repertoire of -1000 odorant receptor (OR) genes. While cell bodies of OSNs expressing a given OR gene are dispersed over a wide area in the olfactory epithelium, their axons converge onto a small number of the -1800 glomeruli in the olfactory bulb of the mouse. In 1996 a genetic approach was developed to image selectively OSNs that express a particular OR gene: the OR gene P2 was modified genetically such that the axonal marker taulacZ is co-expressed with P2, providing a histochemical assay to trace axons of P2-expressing OSNs. Sorting out -1000 populations of OSNs, each expressing a distinct OR gene, onto -1800 glomeruli represents a phenomenal wiring problem. Gene-targeting experiments have suggested that the OR is a critical determinant of axonal convergence to glomeruli, but it is not the only determinant. The overall aim of our studies continues to be the elucidation of the wiring problem in the olfactory system, with a specific focus on the role of ORs in this process. The hypotheses to be tested are first, that axonal convergence to glomeruli is a multifactorial process, determined in part by the expressed OR, and second, that the olfactory system is heterogeneous and not composed of -1000 circuits that develop in identical ways. The approach is developmental and based on genetic manipulation of the mouse. The following specific aims are proposed: 1) Can the heterogeneity in the olfactory system be discerned during development? 2) Do the local permutations in the glomerular array have a developmental origin? 3) What is the contribution of neuropilins and OCAM to the process of glomerular convergence? 4) Can the role of ORs in axon guidance be distinguished from their function in olfaction? As the brain must be wired properly in order to function properly, the proposed studies will thus be relevant for understanding and treating neurological and psychiatric disorders.